U.S. patent application number 10/416980 was filed with the patent office on 2004-02-26 for composition for sustained delivery of hydrophobic drugs and process for the preparation thereof.
Invention is credited to Kim, Jae-Hong, Lee, Sang-Jun, Seo, Min-Hyo, Yi, Yil-Woong.
Application Number | 20040037885 10/416980 |
Document ID | / |
Family ID | 19702771 |
Filed Date | 2004-02-26 |
United States Patent
Application |
20040037885 |
Kind Code |
A1 |
Seo, Min-Hyo ; et
al. |
February 26, 2004 |
Composition for sustained delivery of hydrophobic drugs and process
for the preparation thereof
Abstract
A composition for the sustained delivery of a drug comprising an
amphiphilic diblock copolymer; a poorly water-soluble drug; a
biodegradable polymer; and liquid poly(ethylene glycol) or
functional derivatives thereof and a process for preparing the
composition are disclosed. When administered into a particular body
site, the composition forms an implant containing the drug and drug
containing polymeric micelles, which are slowly released from the
implant to maintain a constant drug concentration for an extended
period of time.
Inventors: |
Seo, Min-Hyo; (Taejeon,
KR) ; Yi, Yil-Woong; (Taejeon, KR) ; Lee,
Sang-Jun; (Chungcheongnam-do, KR) ; Kim,
Jae-Hong; (Taejeon, KR) |
Correspondence
Address: |
M Wayne Western
Thorpe North & Western
PO Box 1219
Sandy
UT
84091-1219
US
|
Family ID: |
19702771 |
Appl. No.: |
10/416980 |
Filed: |
May 15, 2003 |
PCT Filed: |
December 7, 2001 |
PCT NO: |
PCT/KR01/02121 |
Current U.S.
Class: |
424/486 |
Current CPC
Class: |
A61K 9/0024 20130101;
A61P 35/00 20180101; A61K 9/1075 20130101 |
Class at
Publication: |
424/486 |
International
Class: |
A61K 009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 7, 2000 |
KR |
2000/74098 |
Claims
What is claimed is:
1. A liquid polymeric composition for the sustained delivery of a
poorly water-soluble drug comprising: i) an amphiphilic diblock
copolymer; ii) a poorly water-soluble drug; iii) a biodegradable
polymer; and, iv) liquid poly(ethylene glycol) or a functional
derivative thereof; wherein said amphiphilic diblock copolymer,
said poorly water-soluble drug and said biodegradable polymer are
dissolved or dispersed in said liquid poly(ethylene glycol) or a
functional derivative thereof; and wherein said composition, upon
being injected into a body, forms an implant containing polymeric
micelles wherein said poorly water-soluble drugs are physically
trapped.
2. The composition according to claim 1, wherein said amphiphilic
diblock copolymer is composed of a hydrophilic polyalkylene glycol
block and a hydrophobic biodegradable polymer block.
3. The composition according to claim 2, wherein said hydrophilic
polyalkylene glycol block is a member selected from the group
consisting of polyethylene glycol, monoalkoxypolyethylene glycol
and monoacyloxypolyethylene glycol, and said hydrophobic
biodegradable polymer block is a member selected from the group
consisting of polylactides, polycaprolactone,
poly(lactide-co-glycolide), poly(lactide-co-caprolactone),
poly(lactide-co-p-dioxanone), polyorthoesters, polyanhydrides,
poly(amino acid) and polycarbonates.
4. The composition of claim 3, wherein said hydrophilic
polyalkylene glycol block and said hydrophobic biodegradable
polymer block have molecular weights of 500 to 20,000 Daltons,
respectively.
5. The composition according to claim 1, wherein the content of
said amphiphilic diblock copolymer is within the range of 3 to 70%
by weight based on the total weight of the composition.
6. The composition according to claim 1, wherein said poorly
water-soluble drug is selected from the group consisting of
anticancer agents, antifungal agents, steroids, anti-inflammatory
agents, sex hormones, immunosuppressants, antiviral agents,
anesthetics, anti-emetics and anti-histamines, having solubilities
in water of 10 mg/ml or less at ambient temperatures.
7. The composition of claim 6, wherein said poorly water-soluble
drug is a member selected from the group consisting of paclitaxel,
docetaxel, doxorubicin, cisplatin, carboplatin, 5-FU, etoposide,
camptothecin, testosterone, estrogen, estradiol, triamcinolone
acetonide, hydrocortisone, dexamethasone, prednisolone,
betamethasone, cyclosporines and prostaglandins.
8. The composition according to claim 1, wherein the content of
said poorly water-soluble drug is within the range of 0.1 to 50% by
weight based on the total weight of the amphiphilic diblock
copolymer.
9. The composition according to claim 1, wherein said biodegradable
polymer is a polylactide, polycaprolactone or
poly(lactide-co-glycolide), or a mixture thereof.
10. The composition according to claim 1, wherein the content of
the biodegradable polymer is within the range of 5 to 80% by weight
based on the total weight of the composition.
11. The composition according to claim 1, wherein said
biodegradable polymer has a molecular weight of 500 to 50,000
Daltons.
12. The composition of claim 1, wherein the content of the liquid
poly(ethylene glycol) is within the range of 5 to 80% by weight
based on the total weight of the composition.
13. The composition according to claim 1, wherein said liquid
poly(ethylene glycol) has a molecular weight of 100 to 3,000
Daltons.
14. The composition according to claim 1, wherein said liquid
poly(ethylene glycol) is one or more member selected from the group
consisting of liquid polyethylene glycol, and alkyl and alkyl
derivatives thereof.
15. A liquid polymeric composition for the sustained delivery of a
poorly water-soluble drug comprising: i) 3 to 70 wt % based on the
total weight of the composition of an amphiphilic diblock
copolymer; ii) 0.1 to 50 wt % based on the total weight of the
amphiphilic diblock copolymer of a poorly water-soluble drug; iii)
5 to 80 wt % based on the total weight of the composition a
biodegradable polymer; and, iv) 5 to 80 wt % based on the total
weight of the composition of liquid poly(ethylene glycol) or a
functional derivative thereof; wherein said amphiphilic diblock
copolymer, said poorly water-soluble drug and said biodegradable
polymer are dissolved or dispersed in said liquid poly(ethylene
glycol) or a functional derivative thereof; and wherein said
composition, upon being injected into a body, forms an implant
containing polymeric micelles wherein said poorly water-soluble
drugs are physically trapped.
16. The composition according to claim 15, wherein said amphiphilic
diblock copolymer is composed of a hydrophilic polyalkylene glycol
block and a hydrophobic biodegradable polymer block having
molecular weights of 500 to 20,000 Daltons, respectively.
17. The composition according to claim 16, wherein said hydrophilic
polyalkylene glycol block is a member selected from the group
consisting of polyethylene glycol, monoalkoxypolyethylene glycol
and monoacyloxypolyethylene glycol, and said hydrophobic
biodegradable polymer block is a member selected from the group
consisting of polylactides, polycaprolactone,
poly(lactide-co-glycolide), poly(lactide-co-caprolactone),
poly(lactide-co-p-dioxanone), polyorthoesters, polyanhydrides,
poly(amino acid) and polycarbonates.
18. The composition according to claim 15, wherein said poorly
water-soluble drug is selected from the group consisting of
anticancer agents, antifungal agents, steroids, anti-inflammatory
agents, sex hormones, immunosuppressants, antiviral agents,
anesthetics, anti-emetics and anti-histamines, having solubilities
in water of 10 mg/ml or less at ambient temperatures.
19. The composition of claim 18, wherein said poorly water-soluble
drug is a member selected from the group consisting of paclitaxel,
docetaxel, doxorubicin, cisplatin, carboplatin, 5-FU, etoposide,
camptothecin, testosterone, estrogen, estradiol, triamcinolone
acetonide, hydrocortisone, dexamethasone, prednisolone,
betamethasone, cyclosporines and prostaglandins.
20. The composition according to claim 15, wherein said
biodegradable polymer is a member selected from the group
consisting of polylactide, polycaprolactone,
poly(lactide-co-glycolide) and a mixture thereof and has a
molecular weight of 500 to 50,000 Daltons.
21. The composition according to claim 15, wherein said liquid
poly(ethylene glycol) has a molecular weight of 100 to 3,000
Daltons and is one or more member selected from the group
consisting of liquid polyethylene glycol, and alkyl and alkyl
derivatives thereof.
22. A process for preparing the composition according to claim 1,
comprising the steps of: i) mixing liquid polyethylene glycol or
derivatives thereof, an amphiphilic diblock copolymer and a poorly
water-soluble drug to form a polymeric micellar polyethylene glycol
liquid composition; ii) dissolving or dispersing a biodegradable
polymer in liquid poly(ethylene glycol) or derivatives thereof to
form a biodegradable polymer liquid composition; and iii) mixing
together said liquid compositions of steps i) and ii).
23. The process according to claim 22, wherein said amphiphilic
diblock copolymer is composed of a hydrophilic polyalkylene glycol
block and a hydrophobic biodegradable polymer block.
24. The process according to claim 23, wherein said hydrophilic
polyalkylene glycol block is a member selected from the group
consisting of polyethylene glycol, monoalkoxypolyethylene glycol
and monoacyloxypolyethylene glycol, and said hydrophobic
biodegradable polymer block is a member selected from the group
consisting of polylactides, polycaprolactone,
poly(lactide-co-glycolide), poly(lactide-co-caprolactone),
poly(lactide-co-p-dioxanone), polyorthoesters, polyanhydrides,
poly(amino acid) and polycarbonates.
25. The process of claim 24, wherein said hydrophilic polyalkylene
glycol block and said hydrophobic biodegradable polymer block have
molecular weights of 500 to 20,000 Daltons, respectively.
26. The process according to claim 22, wherein the content of said
amphiphilic diblock copolymer is within the range of 3 to 70% by
weight based on the total weight of the composition.
27. The process according to claim 22, wherein said poorly
water-soluble drug is selected from the group consisting of
anticancer agents, antifungal agents, steroids, anti-inflammatory
agents, sex hormones, immunosuppressants, antiviral agents,
anesthetics, anti-emetics and anti-histamines, having solubilities
in water of 10 mg/ml or less at ambient temperatures.
28. The process of claim 27, wherein said poorly water-soluble drug
is a member selected from the group consisting of paclitaxel,
docetaxel, doxorubicin, cisplatin, carboplatin, 5-FU, etoposide,
camptothecin, testosterone, estrogen, estradiol, triamcinolone
acetonide, hydrocortisone, dexamethasone, prednisolone,
betamethasone, cyclosporines and prostaglandins.
29. The process according to claim 22, wherein the content of said
poorly water-soluble drug is within the range of 0.1 to 50% by
weight based on the total weight of the amphiphilic diblock
copolymer.
30. The process according to claim 22, wherein said biodegradable
polymer is a polylactide, polycaprolactone or
poly(lactide-co-glycolide), or a mixture thereof.
31. The process according to claim 22, wherein the content of the
biodegradable polymer is within the range of 5 to 80% by weight
based on the total weight of the composition.
32. The process according to claim 22, wherein said biodegradable
polymer has a molecular weight of 500 to 50,000 Daltons.
33. The process of claim 22, wherein the content of the liquid
poly(ethylene glycol) is within the range of 5 to 80% by weight
based on the total weight of the composition.
34. The process according to claim 22, wherein said liquid
poly(ethylene glycol) has a molecular weight of 100 to 3,000
Daltons.
35. The process n according to claim 22, wherein said liquid
poly(ethylene glycol) is one or more member selected from the group
consisting of liquid polyethylene glycol, and alkyl and alkyl
derivatives thereof.
36. A process for preparing the composition according to claim 15,
comprising the steps of: i) mixing liquid polyethylene glycol or
derivatives thereof, an amphiphilic diblock copolymer and a poorly
water-soluble drug to form a polymeric micellar polyethylene glycol
liquid composition; ii) dissolving or dispersing a biodegradable
polymer in liquid poly(ethylene glycol) or derivatives thereof to
form a biodegradable polymer liquid composition; and iii) mixing
together said liquid compositions of steps i) and ii).
37. The process according to claim 36, wherein said amphiphilic
diblock copolymer is composed of a hydrophilic polyalkylene glycol
block and a hydrophobic biodegradable polymer block having
molecular weights of 500 to 20,000 Daltons, respectively.
38. The process according to claim 37, wherein said hydrophilic
polyalkylene glycol block is a member selected from the group
consisting of polyethylene glycol, monoalkoxypolyethylene glycol
and monoacyloxypolyethylene glycol, and said hydrophobic
biodegradable polymer block is a member selected from the group
consisting of polylactides, polycaprolactone,
poly(lactide-co-glycolide), poly(lactide-co-caprolactone),
poly(lactide-co-p-dioxanone), polyorthoesters, polyanhydrides,
poly(amino acid) and polycarbonates.
39. The process according to claim 36, wherein said poorly
water-soluble drug is selected from the group consisting of
anticancer agents, antifungal agents, steroids, anti-inflammatory
agents, sex hormones, immunosuppressants, antiviral agents,
anesthetics, anti-emetics and anti-histamines, having solubilities
in water of 10 mg/ml or less at ambient temperatures.
40. The process of claim 39, wherein said poorly water-soluble drug
is a member selected from the group consisting of paclitaxel,
docetaxel, doxorubicin, cisplatin, carboplatin, 5-FU, etoposide,
camptothecin, testosterone, estrogen, estradiol, triamcinolone
acetonide, hydrocortisone, dexamethasone, prednisolone,
betamethasone, cyclosporines and prostaglandins.
41. The process according to claim 36, wherein said biodegradable
polymer is a member selected from the group consisting of
polylactide, polycaprolactone, poly(lactide-co-glycolide) and a
mixture thereof and has a molecular weight of 500 to 50,000
Daltons.
42. The process according to claim 36, wherein said liquid
poly(ethylene glycol) has a molecular weight of 100 to 3,000
Daltons and is one or more member selected from the group
consisting of liquid polyethylene glycol, and alkyl and alkyl
derivatives thereof.
43. A method for the sustained delivery of a poorly water-soluble
drug to a warm blooded animal comprising preparing the composition
according to claim 1 by i) mixing liquid polyethylene glycol or
derivatives thereof, an amphiphilic diblock copolymer and a poorly
water-soluble drug to form a polymeric micellar polyethylene glycol
liquid composition; ii) dissolving or dispersing a biodegradable
polymer in liquid poly(ethylene glycol) or derivatives thereof to
form a biodegradable polymer liquid composition; and iii) mixing
together said liquid compositions of steps i) and ii); and
administering the liquid composition to said warm blooded animal.
Description
[0001] This application claims benefit of PCT application No.
PCT/KR01/02121 filed Dec. 7, 2001 which claims a priority date of
Dec. 7, 2000.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a composition for the
sustained delivery of a hydrophobic drug and to a process for
preparing the same. More specifically, the present invention
relates to a liquid composition for the sustained delivery of a
hydrophobic drug comprising: i) an amphiphilic diblock copolymer;
ii) a hydrophobic drug; iii) a biodegradable polymer; and iv)
liquid polyethylene glycol or derivatives thereof. The amphiphilic
diblock copolymer forms polymeric micelles in the liquid
polyethylene glycol and the hydrophobic drug is physically trapped
within the micelles. Furthermore, the biodegradable polymer forms
matrices in the liquid polyethylene glycol such that the drug
containing micelles in the polyethylene glycol are contained within
the biodegradable polymer matrices. When injected into a living
body, the composition forms a polymeric implant comprising the drug
containing micelles within the polymeric matrices. The micelles and
drug are gradually released from the matrices and the drug is then
slowly released from the micelles in a controlled manner providing
for a constant drug concentration in vivo for an extended period of
time.
[0004] 2. Related Art
[0005] Numerous studies regarding drug delivery systems have been
conducted with a variety of drugs and methods in an effort to
maximize the efficacy and effects of drugs and minimize the side
effects of drugs by efficient administration means and controlling
the rate of drug release.
[0006] Biocompatible, biodegradable polymers have been widely used
in the medical field as surgical sutures, tissue regenerative
induction membranes, protective membranes for the treatment of
wounds, and drug delivery systems. Among biodegradable polymers,
polylactide (PLA), polyglycolide (PGA) and a copolymer (PLGA) of
lactide and glycolide, are all commercially available. They have
good biocompatibility and are decomposable in the body to harmless
materials such as carbon dioxide, water, etc.
[0007] One example of a biodegradable polymeric drug delivery
system is a system wherein a drug is contained in a biodegradable
polymer matrix. These systems have the disadvantage of having to be
surgically implanted. In the form of injectable drug delivery
systems, polymeric microspheres and nanospheres are known in the
art. However, those systems have disadvantages in that they require
special preparation methods. In addition, since the biodegradable
polymers used can only be dissolved in organic solvents,
preparation requires the use of organic solvents harmful to the
human body and therefore any residual solvent remaining after
preparation of the microspheres must be completely removed.
Furthermore, some drugs, such as polypeptides and proteins, may
lose their physiological activity after contacting organic
solvents.
[0008] Most drugs, after administration, must have a constant
plasma concentration in order to provide for the desired
pharmacological effects. In particular, drugs with short half-lives
must be administered frequently to achieve effective plasma
concentrations. For such drugs, sustained delivery formulations
from which the drugs are slowly released to continuously provide
their pharmacological effects, have been developed.
[0009] Many important drugs are hydrophobic and have limited
solubility in water. In order to attain the expected therapeutic
effect from such drugs it is usually required that a solubilized
form of the drug be administered to a patient. Therefore,
solubilization of a poorly water soluble drug is key technology in
the preparation of a formulation for oral or parenteral, especially
intravenous, administration of the drug. Common methods used for
solubilization of poorly water soluble drugs are: i) dissolving the
drug in a co-solvent of a water-miscible organic solvent and water;
ii) modifying the drug to its salt form which is soluble in water;
iii) forming a soluble drug-complex using a complexing agent; iv)
introducing a hydrophilic group into the drug molecule; v)
micellizing the drug in an aqueous medium with a surfactant, and
vi) dispersing the drug in water to form emulsions, liposomes,
nanoparticles and the like [S. Sweetana, et al., Solubility
Principles and Practices for Parenteral Drug Dosage Form
Development, PDA J. Pharm. Sci. & Tech. 60 (1996) 330-342].
[0010] U.S. Pat. No. 5,543,158 discloses a nanoparticle, wherein a
drug is entrapped therein, formed of a block copolymer consisting
of a hydrophilic polyethylene glycol block and a hydrophobic
poly(lactide-co-glycolide) block. The nanoparticle has a
hydrophilic outer shell that can decrease uptake of the drug by the
reticuloendothelial system thus allowing it to remain in the
systemic circulation for an extended period of time. However, in
order to manufacture the formulation, organic solvents harmful to
the human body have to be used in order to dissolve the drugs and
the polymers. Furthermore, the drugs are completely exhausted from
the blood within several days because they are intravascularly
injected.
[0011] X. Zhang et al. reported that a polymeric micelle prepared
with a diblock copolymer of poly(lactic acid) and monomethoxy
poly(ethylene glycol) was useful as a carrier of paclitaxel [X.
Zhang et al., Int. J. Pharm. 132 (1996) 195-206], and Shin et al.
disclose a solubilization method for indomethacin using a diblock
copolymer of poly(ethylene glycol) and polycaprolactone [I. Gyun
Shin et al., J. Contr. Rel. 51 (1998) 13-22]. In these methods, a
poorly water soluble drug is incorporated in a polymeric micelle,
wherein the polymers are biocompatible and biodegradable. According
to their methods, a drug and a block copolymer are dissolved
together in an organic solvent, especially in a water-miscible
organic solvent such as tetrahydrofuran or dimethyl formamide. The
polymeric micelles are prepared by dialyzing the solution in water
first and then freeze-drying the aqueous micellar solution.
Alternatively, a solution of a polymer and drug in a water-miscible
organic solvent, acetonitrile, is prepared. The organic solvent is
slowly evaporated to give a homogeneous drug-polymer matrix and the
matrix is then dispersed in an aqueous medium at ca. 60.degree. C.
to form the polymeric micelles.
[0012] Implants can be directly applied to a particular body site
rather than being intravascularly injected. For example, U.S. Pat.
No. 5,869,079 discloses an implant comprising the poorly
water-soluble drug dexamethasone, a copolymer of lactic acid and
glycolic acid, and hydroxypropyl methylcellulose. In addition, U.S.
Pat. No. 6,004,573 discloses that a PLGA-PEG-PLGA triblock
copolymer made up of hydrophobic poly(lactide-co-glycolide) (PLGA)
blocks and a hydrophilic polyethylene glycol (PEG) block can be
used as an implant for effectively delivering poorly water-soluble
drugs. However, the above formulations fail to provide for
effective plasma concentrations of poorly water-soluble drugs due
to their extremely low solubility in body fluids. Thus, a
composition for use as an implant that can be prepared by a simple
procedure, and which releases the hydrophobic drug over an extended
period of time and which is administered by a single injection and
then decomposes into materials harmless to human body, is
needed.
SUMMARY OF THE INVENTION
[0013] It has been recognized that it would be advantageous to
develop a composition for the sustained delivery of a hydrophobic
drug that is capable of forming an implant when administered into a
particular body site.
[0014] The present invention provides a composition for the
sustained delivery of a hydrophobic drug that forms an implant when
administered into a particular body site and the drug and polymeric
micelles containing the drug are slowly released, in vivo, from the
implant.
[0015] One aspect of the present invention relates to a composition
for the sustained delivery of a poorly water-soluble drug
comprising: i) an amphiphilic diblock copolymer; ii) a poorly
water-soluble drug; and iii) a biodegradable polymer, dispersed or
suspended in liquid poly(ethylene glycol) or a suitable derivative
thereof.
[0016] According to the present invention, the amphiphilic diblock
copolymer forms polymeric micelles in the liquid polyethylene
glycol and the poorly water-soluble drug is trapped within the
polymeric micelles. In addition, when administered into the body,
the biodegradable polymer develops into an implant by forming
matrices in the liquid polyethylene glycol. The drug and polymeric
micelles containing the drug are slowly released in vivo from the
implant matrices over sustained periods of time and the polymers
then decompose into materials harmless to the human body.
[0017] The amphiphilic diblock copolymer in the present invention
is preferably a diblock copolymer of a hydrophilic poly(alkylene
glycol) block and a hydrophobic biodegradable polymer block
dispersed or suspended in a poly(ethylene glycol) matrix, or its
derivatives.
[0018] The term poly(ethylene glycol) or PEG, as used herein, shall
also be deemed to include derivatives of PEG unless otherwise
specifically stated. Such derivatives will be more specifically
described in the disclosure that follows. Since only the
hydrophilic component block, not the hydrophobic component block,
of the copolymer has an affinity or attraction for the
poly(ethylene glycol) matrix, the block copolymer forms a
core-shell structure wherein the hydrophobic biodegradable polymer
block occupies the inner core and the hydrophilic poly(alkylene
glycol) block forms the outer shell in the poly(ethylene glycol)
medium. In addition, the biodegradable polymer employed in the
present invention forms matrices in liquid polyethylene glycol and
controls the release rate of the hydrophobic drug and the drug
containing polymeric micelles.
[0019] The content of the amphiphilic diblock copolymer is
preferably within the range of 3 to 70% by weight and more
preferably from 5 to 50% by weight, based on the total weight of
the composition. The drug content is within the range of 0.1 to 50%
by weight and is preferably 1 to 30% by weight, based on the weight
of the amphiphilic diblock copolymer. The content of the
biodegradable polymer is within the range of 5 to 80% by weight and
is preferably 10 to 70% by weight, based on the total weight of the
composition. The molecular weight of the biodegradable polymer is
within the range of 500 to 50,000 Daltons and is preferably from
1,000 to 30,000 Daltons. The content of liquid polyethylene glycol
employed in the present invention is within the range of 5 to 80%
by weight and is preferably from 10 to 60% by weight, based on the
total weight of the composition.
[0020] The composition of the present invention forms implants when
administered into a particular body site, and the drug and
polymeric micelles containing the same are slowly released
therefrom. Therefore, a constant concentration of the drug is kept
at the administration site as well as in the circulation thereby
achieving excellent pharmacological effects. Also, no organic
solvent harmful to the human body is involved in the composition or
the preparation process thereof. Moreover, the polymers employed in
the present invention are safely degraded into products harmless to
the human body and are then excreted.
[0021] Additional features and advantages of the invention will be
apparent from the detailed description which follows, taken in
conjunction with the accompanying drawings, which together
illustrate, by way of example, features of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 is a schematic representation of the composition of
the present invention;
[0023] FIG. 2 schematically illustrates drug release from a tissue
implant formed when the composition of the present invention is
injected into the body;
[0024] FIG. 3 illustrates the results of in vitro drug release
tests for the composition of the present invention;
[0025] FIG. 4 illustrates the anticancer activity of the
paclitaxel-containing composition of the present invention against
human ovarian cancer; and,
[0026] FIG. 5 illustrates the anticancer activity of the
paclitaxel-containing composition of the present invention against
human prostatic carcinoma.
DETAILED DESCRIPTION
[0027] Reference will now be made to the exemplary embodiments
illustrated in the drawings, and specific language will be used
herein to describe the same. It will nevertheless be understood
that no limitation of the scope of the invention is thereby
intended. Alterations and further modifications of the inventive
features illustrated herein, and additional applications of the
principles of the inventions as illustrated herein, which would
occur to one skilled in the relevant art and having possession of
this disclosure, are to be considered within the scope of the
invention.
[0028] The present invention relates to a composition for the
sustained delivery of a poorly water-soluble drug comprising: i) an
amphiphilic diblock copolymer; ii) a poorly water-soluble drug; and
iii) a biodegradable polymer, dispersed or suspended in liquid
poly(ethylene glycol). When injected into a living body, the
composition of the present invention forms a polymeric implant
which contains a poorly water soluble drug and drug-containing
micelles. The drug and the drug containing micelles are slowly
released over a prolonged period of time and the polymers are
decomposed into materials harmless to the human body.
[0029] The block copolymer portion of such compositions has a
core-shell structure wherein the hydrophobic biodegradable polymer
block occupies the inner core and the hydrophilic poly(alkylene
glycol) block forms the outer shell in the hydrophilic liquid
poly(ethylene glycol) matrix or medium. The poly(ethylene glycol)
functions as a dispersant to facilitate water solubility and the
block copolymer portion of the composition forms a micellular
structure in body fluids or in an aqueous medium. When a poorly
water soluble drug is added to the composition, it is contained
within the inner hydrophobic core. Accordingly, a pharmaceutical
formulation containing the composition of the present invention is
capable of effectively solubilizing a poorly water soluble drug in
a body fluid or in an aqueous medium by forming a micelle, wherein
the drug is entrapped in the core of the micelle. In addition, the
biodegradable polymer employed in the present invention forms
matrices in liquid polyethylene glycol which controls the release
rate of the hydrophobic drug and polymeric micelles containing the
hydrophobic drug, from the implant site into the body.
[0030] In summary, the present invention is a combination of an
amphiphilic diblock copolymer and a biodegradable polymer, as
defined herein, suspended in a liquid poly(ethylene glycol) medium.
The amphiphilic diblock copolymer comprises a hydrophilic
poly(alkylene glycol) component and a hydrophobic biodegradable
polymer component. The poly(ethylene glycol) medium facilitates the
dispersion of the diblock copolymer which forms a polymeric
micelle. When a poorly water soluble drug is added to the
composition, the drug is solubilized by incorporating the drug into
the inner core of the micelle. The composition of the present
invention forms a polymeric implant when injected into a living
body, from which the drug and the drug-containing micelles are
slowly released over a prolonged period of time and the implant is
then decomposed into materials harmless to the human body and
excreted.
[0031] The polyalkylene glycol suitable for the hydrophilic
component of the amphiphilic diblock copolymer of the present
invention is a member selected from the group consisting of
polyethylene glycol, monoalkoxy polyethylene glycol, or monoacyloxy
polyethylene glycol wherein the molecular weight of the
polyalkylene glycol is preferably within the range of
500.about.20,000 Daltons, and more preferably within the range of
1,000.about.15,000 Daltons. The content of the hydrophilic
component of the amphiphilic diblock copolymer is within the range
of 30.about.80 wt %, preferably 40.about.70 wt %, based on the
total weight of the block copolymer.
[0032] The hydrophobic biodegradable polymer component of the
amphiphilic diblock copolymer of the present invention is a member
selected from the group consisting of polylactides,
polycaprolactone, copolymers of lactide and glycolide, copolymers
of lactide and caprolactone, copolymers of lactide and
1,4-dioxan-2-one, polyorthoesters, polyanhydrides,
polyphosphazines, poly(amino acid)s and polycarbonates. Preferably,
the hydrophobic biodegradable polymer component of the copolymer of
the present invention is a member selected from the group
consisting of polylactides, polycaprolactone, a copolymer of
lactide and glycolide, a copolymer of lactide and caprolactone, and
a copolymer of lactide and 1,4-dioxan-2-one. The molecular weight
of the hydrophobic biodegradable polymer component is preferably
within the range of 500.about.20,000 Daltons, and more preferably
within the range of 1,000.about.15,000 Daltons.
[0033] The amphiphilic diblock copolymer of the present invention
can be synthesized by polymerizing lactone type heterocyclic esters
and monoalkoxypolyethylene glycols at a temperature of 80 to
130.degree. C. using stannous octoate (SnOct.sub.2) as a catalyst
[E. Piskin et al., Novel PDLA/PEG copolymer micelles as drug
carriers, J. of Biomater. Sci. Polymer Edn. 7 (4) (1995) 359-373].
For example, they may be prepared via ring opening bulk
polymerization of one of the cyclic ester monomers, such as
lactide, glycolide, or 1,4-dioxan-2-one with monomethoxy
poly(ethylene glycol) (mPEG) or poly (ethylene glycol) (PEG) in the
presence of stannous octoate as a catalyst at 80.about.130.degree.
C. When the 1,4-dioxan-2-one is used as the monomer, the preferable
reaction temperature is 80.about.110.degree. C. When a copolymer of
1,4-dioxan-2-one and lactide is used, the 1,4-dioxan-2-one monomer
is first reacted with mPEG or PEG at 100.about.130.degree. C., the
lactide monomer is then slowly added to increase the degree of
polymerization of 1,4-dioxan-2-one. Since the conversion of the
1,4-dioxan-2-one monomer is 50.about.60%, the added amount of this
monomer should be more than the calculated amount when the two
monomers, 1,4-dioxan-2-one and lactide, are added together. The
block copolymer product is dissolved in dichloromethane or acetone,
precipitated in diethyl ether, hexane, pentane, or heptane,
followed by drying.
[0034] The liquid poly(ethylene glycol) or its derivatives, used as
a dispersion medium for the composition of the present invention,
have high attraction for the hydrophilic component of the diblock
copolymer and preferably, have melting temperature of below about
40.degree. C., and molecular weights of 100.about.3,000 Daltons and
more preferably 200.about.2,000 Daltons. The term "liquid" used
herein is defined as the liquid phase at a temperature of
50.degree. C. Accordingly, the liquid polyethylene glycol employed
in the present invention may be one or more selected from the group
consisting of polyethylene glycol, and alkyl or allyl derivatives
thereof, each of which is liquid at 50.degree. C.
[0035] As shown in FIG. 1, the biodegradable polymer employed in
the present invention forms matrices in liquid polyethylene glycol
and controls the rate of release of the drug and polymeric micelles
containing the same. The biodegradable polymer employed in the
present invention should be biocompatible, be degradable into
products harmless to the human body after a given time in vivo, and
be soluble or uniformly dispersible in liquid polyethylene glycol
of low molecular weight. Examples of the biodegradable polymer
include polylactide, polycaprolactone, poly(lactide-co-glycolide)
and mixtures thereof. The content of the biodegradable polymer is
within the range of 5 to 80% by weight and preferably from 10 to
70% by weight, based on the total weight of the composition. The
molecular weight of the biodegradable polymer is within the range
of 500 to 50,000 Daltons and is preferably from 1,000 to 30,000
Daltons.
[0036] The content of the amphiphilic diblock copolymer is
preferably within the range of 3 to 70% by weight and more
preferably is from 5 to 50% by weight, based on the total weight of
the composition. The drug content is within the range of 0.1 to 50%
by weight and preferably from 1 to 30% by weight, based on the
weight of the amphiphilic diblock copolymer. The content of the
biodegradable polymer is within the range of 5 to 80% by weight and
is preferably from 10 to 70% by weight, based on the total weight
of the composition. The content of liquid polyethylene glycol
employed in the present invention is within the range of 5 to 80%
by weight and is preferably from 10 to 60% by weight, based on the
total weight of the composition.
[0037] When introduced into the body, the composition of the
present invention forms an implant. As illustrated in FIG. 2, the
poorly water-soluble drugs are entrapped within the polymeric
micelles formed by the amphiphilic diblock copolymer which in turn
are embedded in the biodegradable polymer matrix and the liquid
polyethylene glycol (PEG) medium. Therefore, the drugs and/or
drug-containing micelles are slowly released from the polymeric
micelles and/or from the implant thereby providing a constant drug
circulation concentration for an extended period of time. Thus the
compositions of the present invention are especially useful for the
sustained delivery of poorly water soluble drugs having
solubilities of less than 10 mg/mL at ambient temperatures.
Examples of these hydrophobic drugs include anticancer agents,
antiinflammatory agents, antifungal agents, antiemetics,
antihypertensive agents, sex hormones, and steroids. Typical
examples of these hydrophobic drugs are: anticancer agents such as
paclitaxel, docetaxel, camptothecin, doxorubicin, daunomycin,
cisplatin, 5-fluorouracil, mitomycin, methotrexate, and etoposide;
antiinflammatory agents such as indomethacin, ibuprofen,
ketoprofen, flubiprofen, dichlofenac, piroxicam, tenoxicam,
naproxen, aspirin, and acetaminophen; antifungal agents such as
itraconazole, ketoconazole and amphotericin; sex hormons such as
testosterone, estrogen, progesterone, and estradiol; steroids such
as dexamethasone, prednisolone, betamethasone, triamcinolone
acetonide and hydrocortisone; antihypertensive agents such as
captopril, ramipril, terazosin, minoxidil, and parazosin;
antiemetics such as ondansetron and granisetron; antibiotics such
as metronidazole, and fusidic acid; cyclosporines; prostaglandins;
and biphenyl dimethyl dicarboxylic acid.
[0038] The rate of release of a drug and of the polymeric micelles
containing the same, depends on the composition of the
biodegradable polymer and the molecular weight and content thereof,
because the degradation rate depends on the kind of polymer
employed and the viscosity of the matrix depends on the molecular
weight and content of the polymer employed.
[0039] Since the composition of the present invention contains a
biocompatible polymer which is degradable after a given time into
products that are harmless to the human body and is excreted from
the body, the drug release rate can be controlled by adjusting the
content of each component. The composition forms implants when
injected into a particular body site, the drug and the polymeric
micelles containing the same, are slowly released from the
implants, thereby keeping a constant concentration of the drug at
the implantation site as well as in the circulation for an extended
period of time. Therefore, the composition of the present invention
can provide for excellent pharmacological effects. That is, as
shown in the following Example 19 (drug release test), in a
composition without the amphiphilic diblock copolymer (Comparative
Example 1), only an extremely small amount of the drug is released
into an aqueous medium. In a composition without the biodegradable
polymeric matrix (Comparative Example 2), the drug is completely
released into the aqueous medium within 24 hours. By contrast, the
present composition can control the release of the drug and the
polymeric micelles containing the same, by adjusting the content of
each component. Therefore, the present composition provides for a
constant concentration of the drug for an extended period of
time.
[0040] The composition of the present invention may be prepared as
follows. An amphiphilic diblock copolymer, and a poorly
water-soluble drug are mixed in liquid polyethylene glycol and
stirred to prepare a polymeric micellar composition (Composition A)
containing the poorly water-soluble drug entrapped therein. In the
above process, the stirring is carried out, preferably at a
temperature of 40 to 80.degree. C., for 30 to 60 minutes. A
biodegradable polymer is dissolved or dispersed in liquid
polyethylene glycol to prepare Composition B. Then, Composition A
is mixed with Composition B and stirred to prepare a composition
for the sustained delivery of a drug of the present invention. In
the above process the stirring is carried out, preferably at a
temperature of 40 to 80.degree. C., for 1 to 2 hours.
[0041] The composition of the present invention may be injected
into a particular site of the human body by means of a syringe or
catheter. The polymers contained in the present composition are
safe in that the United States Food and Drug Administration (FDA)
has allowed them for in vivo use. The polymers have the additional
advantage in that they are hydrolyzed into products readily
excreted from the body.
[0042] While the following preparations and examples are provided
for the purpose of illustrating certain aspects of the present
invention, they are not to be construed as limiting the scope of
the appended claims.
EXAMPLES
[0043] Synthesis of Amphiphilic Diblock copolymer
[0044] Preparation 1: mPEG-PLA (MW 2,000-1,800)
[0045] 25 g of methoxypolyethylene glycol (MPEG, MW=2,000) and 25 g
of D,L-lactide recrystallized from ethyl acetate were added to a
round-bottomed flask equipped with a pedal stirrer. Thereto was
added 0.25 g of stannous octoate (SnOct.sub.2) dissolved in 5 ml of
toluene. The flask was then heated to 120.degree. C. in an oil bath
to evaporate excess toluene. Subsequently, the reaction was
performed under reduced pressure (25 mmHg) for 6 hours. The
resulting product was dissolved in chloroform. The solution was
slowly added to cold diethyl ether (4.degree. C.) to precipitate
the formed polymer. The polymer was purified by repeating the
dissolution-precipitation process twice and was then dried in a
vacuum oven (0.1 mmHg) for 24 hours. The molecular weight of the
copolymer (mPEG-PLA) was identified by Nuclear Magnetic Resonance
(NMR) Spectroscopy.
[0046] Preparation 2: mPEG-PLA (MW 3,400-2,500)
[0047] According to substantially the same method as in Preparation
1, a copolymer (mPEG-PLA) was prepared using 25 g of
methoxypolyethylene glycol (mPEG, MW=3,400), 20 g of D,L-lactide,
and 0.20 g of stannous octoate, and the molecular weight of the
copolymer was identified.
[0048] Preparation 3: mPEG-PLA (MW 5,000-4,000)
[0049] According to substantially the same method as in Preparation
1, a copolymer (mPEG-PLA) was prepared using 25 g of
methoxypolyethylene glycol (mPEG, MW=5,000), 22 g of D,L-lactide,
and 0.22 g of stannous octoate, and the molecular weight of the
copolymer was identified.
[0050] Preparation 4: mPEG-PLA (MW 8,000-6,000)
[0051] According to substantially the same method as in Preparation
1, a copolymer (mPEG-PLA) was prepared using 25 g of
methoxypolyethylene glycol (mPEG, MW=8,000), 20 g of D,L-lactide,
and 0.20 g of stannous octoate, and the molecular weight of the
copolymer was identified.
[0052] Preparation 5: MPEG-PCL (MW 5,000-4,000)
[0053] According to substantially the same method as in Preparation
1, a copolymer (mPEG-PCL) was prepared using 25 g of
methoxypolyethylene glycol (mPEG, MW=5,000), 20 g of
.epsilon.-caprolactone, and 0.20 g of stannous octoate, and the
molecular weight of the copolymer was identified.
[0054] Preparation 6: mPEG-PLGA (MW 5,000-4,000, LA/GA=7/3)
[0055] According to substantially the same method as in Preparation
1, a copolymer (mPEG-PLGA) was prepared using 25 g of
methoxypolyethylene glycol (mPEG, MW=5,000), 15 g of D,L-lactide, 7
g of glycolide and 0.22 g of stannous octoate, and the molecular
weight of the copolymer was identified.
[0056] Preparation 7: mPEG-PLDO (MW 5,000-4,000, LA/DO=7/3)
[0057] According to substantially the same method as in Preparation
1, a copolymer (mPEG-PLDO) was prepared using 25 g of
methoxypolyethylene glycol (mPEG, MW=5,000), 15 g of D,L-lactide, 7
g of 1-p-dioxanone and 0.22 g of stannous octoate, and the
molecular weight of the copolymer was identified.
[0058] Preparation of Biodegradable Polymer Controlling Release
Rate
[0059] Preparation 8: PLA (MW 4,000)
[0060] 30 g of lactic acid was added to a round-bottomed flask
equipped with a pedal stirrer. Thereto was added 0.15 g of antimony
oxide (Sb.sub.2O.sub.3). The flask was equipped with a distillation
tube, and the temperature was slowly increased. The reaction was
performed at 160.degree. C. for 10 hours. Subsequently, the
reaction was further performed under reduced pressure (25 mmHg) for
an additional 6 hours. The resulting product was dissolved in
chloroform. The solution was slowly added to cold diethyl ether
(4.degree. C.) to precipitate the formed polymer. The polymer was
purified by repeating the dissolution-precipitation process twice
and then the polymer was dried in a vacuum oven (0.1 mmHg) for 24
hours. The molecular weight of the polymer (PLA) was identified by
Nuclear Magnetic Resonance (NMR) Spectroscopy.
[0061] Preparation 9: PLGA (MW 4,000, LA/GA=7/3)
[0062] According to substantially the same method as in Preparation
8, a PLGA polymer was prepared using 21 g of lactic acid and 9 g of
glycolic acid, and the molecular weight of the copolymer was
identified.
[0063] Preparation of Drug Composition
Example 1
Paclitaxel Containing Composition
[0064] In a round-bottomed flask equipped with a pedal stirrer were
mixed 90 mg of the amphiphilic diblock copolymer (mPEG-PLA)
prepared in Preparation 1, 10 mg of paclitaxel as a poorly
water-soluble drug and 100 mg of a liquid polyethylene glycol (PEG,
MW 300). The mixture was then stirred at 60.degree. C. for 30
minutes to prepare Composition A. According to the same method as
above, 100 mg of polylactide (PLA, MW 4,000) as a biodegradable
polymer that forms matrices, was dissolved in 100 mg of the same
polyethylene glycol used to prepare Composition B. Composition A
was mixed with Composition B and stirred at 60.degree. C. for 1
hour to prepare a transparent viscous liquid composition.
Examples 2 to 18
[0065] Poorly water-soluble drug containing compositions were
prepared using the ingredients and the contents as listed in Table
1 below, according to substantially the same method as in Example
1.
Comparative Examples 1 and 2
[0066] Poorly water-soluble drug containing compositions were
prepared using the ingredients and the contents as listed in Table
1 below.
1 TABLE 1 Amphiphilic diblock Polymeric copolymer Drug PEG matrix*
Ex- mPEG-PLA (MW Paclitaxel PEG (MW PLA 100 ample 1 2,000-1,800) 90
mg 10 mg 300) 200 mg mg Ex- mPEG-PLA (MW Paclitaxel PEG (MW PLA 100
ample 2 2,000-1,800) 90 mg 10 mg 300) 300 mg mg Ex- mPEG-PLA (MW
Paclitaxel PEG (MW PLA 300 ample 3 2,000-1,800) 90 mg 10 mg 600)
400 mg mg Ex- mPEG-PLA (MW Paclitaxel PEG (MW PLA 600 ample 4
2,000-1,800) 90 mg 10 mg 600) 400 mg mg Ex- mPEG-PLA (MW Paclitaxel
PEG (MW PLA 300 ample 5 3,400-2,500) 90 mg 10 mg 300) 400 mg mg Ex-
mPEG-PLA (MW Paclitaxel PEG (MW PLA 600 ample 6 3,400-2,500) 90 mg
10 mg 300) 400 mg mg Ex- mPEG-PLA (MW Paclitaxel PEG (MW PLA 900
ample 7 3,400-2,500) 90 mg 10 mg 300) 400 mg mg Ex- mPEG-PLA (MW
Paclitaxel PEG (MW PLA ample 8 3,400-2,500) 90 mg 10 mg 300) 400 mg
1.200 mg Ex- mPEG-PLA (MW Paclitaxel PEG (MW PLA ample 9
3,400-2,500) 90 mg 10 mg 300) 600 mg 1,200 mg Ex- mPEG-PLA (MW
Paclitaxel PEG (MW PLA 600 ample 10 3,400-2,500) 90 mg 10 mg 600)
400 mg mg Ex- mPEG-PLA (MW Paclitaxel PEG (MW PLA 600 ample 11
3,400-2,500) 90 mg 10 mg 800) 400 mg mg Ex- mPEG-PLA (MW Paclitaxel
PEG (MW PLGA 600 ample 12 3,400-2,500) 95 mg 5 mg 300) 400 mg mg
Ex- mPEG-PLA (MW Indo- PEG (MW PLA 600 ample 13 3,400-2,500) 90 mg
methacin 300) 400 mg mg 10 mg Ex- mPEG-PLA (MW Indo- PEG (MW PLA
900 ample 14 3,400-2,500) 90 mg methacin 300) 400 mg mg 10 mg Ex-
mPEG-PLA (MW Indo- PEG (MW PLA 900 ample 15 5,000-4,000) 80 mg
methacin 800) 400 mg mg 20 mg Ex- mPEG-PCL (MW Indo- PEG (MW PLA
900 ample 16 5,000-4,000) 80 mg methacin 300) 400 mg mg 20 mg Ex-
mPEG-PLGA (MW Cyclo- PEG (MW PLA 600 ample 17 5,000-4,000, sporine
A 300) 400 mg mg LA/GA = 7/3) 90 mg 10 mg Ex- mPEG-PLDO (MW
Paclitaxel PEG (MW PLA 300 ample 18 5,000-4,000, 5 mg 300) 400 mg
mg LA/DO = 7/3) 95 mg Compara- -- Paclitaxel PEG (MW PLA 300 tive
Ex- 10 mg 600) 400 mg mg ample 1 Compara- mPEG-PLA (MW Paclitaxel
PEG (MW -- tive Ex- 2,000-1,800) 90 mg 10 mg 600) 400 mg ample 2
*PLA: Poly(lactide) (MW 4,000); PLGA: Poly(lactide-co-glycolide)
(MW 4,000, LA/GA = 7/3)
Example 19
Drug Release Test
[0067] 500 mg of each composition obtained from Examples 1 to 18
and Comparative Examples 1 and 2 were added to a capped test tube.
Thereto was then added 15 ml of physiological saline. The
composition solidified at the bottom was transferred into a chamber
at 37.degree. C. The physiological saline was completely refreshed
at regular intervals. An aqueous solution containing the released
drug was centrifuged and the drug was extracted from the
supernatant with methylene chloride. This solution was dried and
the product was redissolved in a 40% aqueous acetonitrile solution.
The concentration of the drug was then measured by HPLC. The
results are shown in the following Table 2 and FIG. 3.
2 TABLE 2 Cumulative Release Rate (%) 10 0 day 1 day 2 days 3 days
5 days 7 days days Example 1 0 33 40 54 65 72 85 Example 2 0 36 47
57 68 76 90 Example 3 0 31 40 51 62 70 82 Example 4 0 23 33 45 53
65 70 Example 5 0 25 36 45 57 68 78 Example 6 0 21 35 42 48 57 65
Example 7 0 18 28 37 42 49 53 Example 8 0 17 24 33 38 42 45 Example
9 0 18 30 40 45 53 57 Example 10 0 21 31 42 47 57 62 Example 11 0
20 31 40 47 55 60 Example 12 0 23 34 46 51 62 69 Example 13 0 23 33
45 55 65 71 Example 14 0 17 31 38 47 53 58 Example 15 0 17 25 33 38
45 50 Example 16 0 18 28 35 43 49 55 Example 17 0 19 30 38 47 53 57
Example 18 0 18 31 38 49 55 60 Comparative 0 2 2 3 3 3 4 Example 1
Comparative 0 100 -- -- -- -- -- Example 2
[0068] As shown in Table 2 and FIG. 3, the drug release rate can be
controlled depending on the content of each ingredient in the
present composition. By contrast, in a composition without an
amphiphilic diblock copolymer (Comparative Example 1), almost no
drug was released into the aqueous medium. Additionally, in a
composition without a biodegradable polymeric matrix (Comparative
Example 2), the drug was completely released into the aqueous
medium within 24 hours.
Example 20
Anticancer Activity on Ovarian Cancer
[0069] In preparing animals to be used in the anticancer activity
test, a piece of human ovarian cancer (SKOV-3, 3-4 mm) was
xenografted onto the right side of female nude mice (Balb/c, an age
of 5-6 weeks, a body weight of 19-21 g) using a 12 gauge troika.
When the volume of the grafted cancer tissue grew to 300-500
mm.sup.3, the composition prepared in Example 1, which was
sterilized using a 0.22 .mu.m filter under aseptic conditions, was
injected intratumorally using a 26-gauge syringe needle. For
comparison, a commercially available paclitaxel formulation, which
is made by dissolving 6 mg of paclitaxel and 527 mg of
Cremophor.RTM. EL in 1 ml ethanol/water (1:1, v/v), was used
intravenously.
[0070] The composition of the present invention (Example 1) was
injected once at a dose of 20 mg/kg (day 0). The commercial
formulation was administered into the tail vein three times (once
on days 0, 1 and 2) at a dose of 20 mg/kg. During administration,
the cancer tissue was measured on the long and short axes at 5-day
intervals. The volume of cancer tissue was calculated by the
formula .pi./6((L+W)/2).sup.3 wherein W represents the length of
the long axis and L represents the length of the short axis. The
compositions of the administered formulations are shown in the
following Table 3. The volume ratio (relative volume) of the cancer
tissue upon administration and at given times after administration
is shown in FIG. 4.
3 TABLE 3 Administration No. of Composition route* Dose mice
Control -- No treatment -- 6 Vehicle Composition of it -- 6 Example
1 without drug Commercial Composition of the iv 20 6 Formulation
commercial mg/kg .times. 3 (iv) formulation Experimental
Composition of it 20 mg/kg 6 Group (it) Example 1 *it:
intratumoral, iv: intravenous
Example 21
Anticancer Activity Against Prostatic Carcinoma
[0071] A piece of human prostatic carcinoma (PC-3, 3-4 mm) was
transplanted onto the right side of male nude mice (Balb/c of 5-6
weeks, 19-21 g). The anticancer activity test was then carried out
according to substantially the same method as in Example 20. The
compositions of the administered formulations are shown in Table 4
below. The volume ratio (relative volume) of the cancer tissue upon
administration and at given times after administration is shown in
FIG. 5.
4 TABLE 4 Administration No. of Composition route* Dose mice
Control -- No treatment -- 6 Vehicle Composition of it -- 6 Example
1 without drug Commercial Composition of the iv 20 6 Formulation
commercial mg/kg .times. 3 (iv) formulation Experimental
Composition of it 60 mg/kg 6 Group (it) Example 1 *it:
intratumoral, iv: intravenous
[0072] As shown in FIGS. 4 and 5, the paclitaxel-containing
composition of the present invention exhibits much higher
anticancer activity than the known formulation.
[0073] It is to be understood that the above-referenced
arrangements are illustrative of application of the principles of
the present invention. Numerous modifications and alternative
arrangements can be devised without departing from the spirit and
scope of the present invention while the present invention has been
shown in the drawings and described above in connection with the
exemplary embodiments(s) of the invention. It will be apparent to
those of ordinary skill in the art that numerous modifications can
be made without departing from the principles and concepts of the
invention as set forth in the claims.
* * * * *